Human olfactory mucosa functions in olfaction, appetite, cognition, behavior, and xenobiotic metabolism. Olfactory deficits can result from aging, viral rhinitis or nasal trauma, and are early symptoms of Alzheimer's disease, Parkinson's disease, and infection with human immunodeficiency virus. 3-Methylindole (3MI, skatole), a digestive tract product of tryptophan metabolism and major odorant from sewage treatment plants, selectively damages olfactory mucosa in mice. The damage produced by 3MI, unlike that produced by many other olfactory toxicants, is persistent and associated with severe nasal fibrosis. The proposed studies of 3MI toxicosis in mice are designed to elucidate the mechanism of olfactory mucosal fibrosis and, in particular, to examine the role of the renin-angiotensin-aldosterone system (RAAS). Three experiments are designed to fulfill specific aims. (1) To detect early lesions that might explain the resultant fibrosis, olfactory mucosa will be examined by light and transmission electron microscopy at 30 min, 1 hr, 2 hr, 4 hr, 6 hr, and 24 hr after injection of 400 mg 3Ml/kg. (2) To correlate activities of the RAAS enzymes, angiotensin converting enzyme (ACE) and 11beta-hydroxysteroid dehydrogenase (11betaHSD), with nasal fibrosis, olfactory mucosa from mice injected with 300 mg 3Ml/kg, 150 mg 3Ml/kg, or vehicle will be examined at 7, 14, 21 and 28 days post-administration. Mitotic index in fibroblasts (7 da only) and severity of olfactory mucosal fibrosis will be compared with enzyme activities. (3) To evaluate the effect of inhibition of RAAS enzymes on the development of olfactory mucosal fibrosis, mice will be injected with 300 mg 3Ml/kg, then treated with the ACE inhibitor, lisinopril; the 11betaHSD inhibitor, glycyrrhizic acid; or vehicle. Activities of ACE and of 11betaHSD will be correlated with histologic evidence of fibrosis and olfactory function. These experiments will enhance understanding of the development of nasal fibrosis. Furthermore, if RAAS enzymes are found to regulate fibroplasia in nasal mucosa as they do in other tissues, pharmaceutical modulation of this system would have potential value in the prevention or resolution of the obliterative fibrosis that follows infectious, traumatic or toxic insult to nasal mucosa.